M.Prasad NaiduMSc Medical Biochemistry,Ph.D.Research Scholar

Pro-insulin, C Peptide,Glucagon, Adiponectin, TNFa,AMPK

Proinsulin Proinsulin (9000 mol wt. peptide) is

synthesized on the ribosomes of pancreatic islet b cells and then transferred to Golgi apparatus,

where during the process of maturation of secretory granules,proinsulin is cleaved by endo-peptidases PC3 (type 1) and PC2 (type 2) into insulin (6000 mol wt) and C-peptide (3000 mol wt.).

Starr and Rubenstein (1974) have studied the metabolism of endogenous proinsulin and insulin in humans .

Compared to insulin , human proinsulin has low biological potency, low avidity for insulin receptors and prolonged half life in circulation.

Predictive value of proinsulin

Haffner SM et al (1993) suggested increased proinsulinas a cardiovascular risk factor in non-diabetic subjects.

Yudkin (1995) showed that a proinsulin : insulin ratio (normal 15%) > 20% is a predictor of future T2DM.

The same was shown by Ramchandran et al (1988) Warham NJ et al (1999), Lele RD et al (2006).

Proinsulin stimulates plasminogen activator inhibiter 1 (PAI-1) secretion and blocks fibrinolysis, thereby increasing risk of cardiovascular micro and macrovascular disease.

A large epidemiological study (IRIS-1, 4265 patients) confirmed that fasting hyperproinsulinemia is a highly specific marker of insulin resistance (Pfutzner et al 2004) hence therapy should focus on reducing insulin resistance.

C peptide

C Peptide is a measure of endogenous insulin secretion,

Normal fasting level is 1-4 ng/ml which rises after meals eg.

Fasting 1.2 ng/ml → 4.7 ng/ml pp1.8 ng/ml → 5 ng/ml pp2 ng/ml → 6.8 ng/ml pp

A biological role for C peptide was suggested by the clinical observation that T1DM with some measurable C peptide have less long-term complications than T1DM patients totally deficient in C-peptide.

Pancreatic / islet cell transplant restored both insulin and C peptide, resulting in amelioration of diabetic nephropathy and neuropathy.

Glucagon

Unger RH (1971, 1974, 1977) has discussed the role of pancreatic islet a and b cell inter-relationship in health and disease and the role of glucogon in diabetes.

Hyperglucagonemia is a characteristic of both T1DM and T2DM.

Impaired a cell regulation leads to excessive glucagon release in the fasting and post-prandial state, with increase hepatic glucose production (HGP) and hyperglycaemia.

The incretin concept was put forward by Crutzfeldl W et al in 1979 indicating the role of two incretins – Glucagon- like peptide1(GLP-1) secreted by intestinal L cells, and Glucose-induced insulinogenic Polypeptide (GIP) secretedn by intestinal – K cells in regulation of islet a and b cell function.

Nauck ME et al in 1993,Dunning BE et al (2005), showed a new approach to achieve normalization of fasting hyperglycemia with exogenous GLP-1 in T2DM and the ability of GLP-1 to increase post-prandial insulin secretion and suppress post-prandial glucagon secretion.

TNFa

Hostamisligil GS et al (1995) showed increased adipose tissue expression of TNFa in human obesity and insulin resistance.

Suzawa M et al (2003) showed that IL-1 and TNFa inhibit the expression and activity of PPARg which is highly expressed in adipose tissue and is the trigger for adipocyte differentiation and proliferation.

Newly formed adipocytes produce adiponectin while distended hypertrophied adipocytes produce leptin, resistin TNFa and IL-6.

Lihn AS et al (2003) have shown that increased TNFa and IL-1 inhibit adipose tissue expression of adiponectin mRNA by 80 per cent thereby lowering plasma adiponectin levels.

In a study of 35 Asian Indian T2DM, high levels of TNFa were a striking feature Normal range of TNFa is 1-20 ng/ml.

19 patients ranged 40-100 ng/ml, 8 more than 100 ng/ml and another 8 more than200ng/ml.

Equally significant was the low adiponectin (< 6 mg/l) and high proinsulin in all of them. (Lele RD et al 2006).

The molecular mechanism of TNF-a induced insulin resistance has been explained (Hostamisigil GS 1999, Shulman GI (2000).

TNFa causes serine phosphorylation of IRS-1 in muscle and IRS-2 in liver thereby abrogating the IRS-PI3K- AKT signaling pathway of insulin action which is necessary for GLUT4 translocation glucose transport and glycogen synthesis.

Role of nutrients

Calder PV (2002) has emphasized the important role of omega 3 PUFAs EPA and DHA in the diet in the suppression of proinflammatory cytokines.

Increased EPA in cell membrane phospholipids suppresses production of prostanoids (PGI2, TXA2, PGD2, PGE2, PGF2a) while increasing the production of prostacyclin and TXA3 which inhibit platelet aggregation.

EPA produces 5- series LT (LTA5, LTB5, LTC5, LTD5, LTE5 which are anti-inflammatory, unlike the LT4 series produced by arachidonic acid, which are proinflammatory.

The adverse impact of replacement of the traditional fat sources in the Indian diet (ghee, mustard oil, coconut oil which have an ideal W6-W3 ratio of 2 : 1) with refined vegetable oils with a very high W6-W3 ratio (even 120 : 1) has contributed to the sharp rise in the metabolic syndrome (Raheja BS 1993).

Adiponectin

Adiponectin, a 244 aminoacid protein produced exclusively by adipocytes, has important role in health and disease.Normal levels (males 7.9 + 0.5 mg/ml females 16.6 + 5 mg/ml).Adiponectin circulates in multimeric forms.

Recent reports have focused on high molecular weight (HMW) adiponectin, which is found to be lower in Asian Indian pregnant women compared to Caucasians (Retna Karon R et al 2006).

Asian Indian T2DM have low adiponectin levels with higher risk for CAD. (Mohan V. et al 2005)

Kadowaki and Yamauchi (2005) have proposed the adiponectin hypothesis for insulin resistance, metabolic syndrome and atherosclerosis.

Conclusion

(1) the utility of routine measurement of pro-insulin to insulin ratio as a specific marker of insulin resistance and predictor of future T2DM, HT and CAD.

(2) routine C-Peptide estimation to determine which T2DM needs insulin and to monitor the effect of newer drugs which promote b cell regeneration

(3) routine estimation of adiponectin and TNFa and monitor response to thiozolidine drugs which increases adiponectin and decreases TNFa production by adipocytes.

(4) crucial role of AMPK – Cellular energy sensor in mediating the beneficial effects of exercise as well as drugs (adiponectin, metformin) in T2DM .

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